Combined C-H functionalization/C-N bond formation route to carbazoles

Article abstract of DOI:10.1021/ja055353i

A new method in which a series of substituted carbazoles is efficiently produced by the combination of an amide and an arene is described. The key feature of this method is the palladium-catalyzed tandem directed C-H functionalization and amide arylation. The method tolerates substitution on either ring of the biaryl amide substrates, and the products can be assembled in a simple two-step protocol from readily available reagents. The Pd(0) species generated are reoxidized to Pd(II) in the presence of Cu(OAc)₂ and an atmosphere of oxygen. Copyright

Full text of DOI:10.1021/ja055353i

Published on Web 10/04/2005
Combined C-H Functionalization/C-N Bond Formation Route to Carbazoles
W. C. Peter Tsang, Nan Zheng, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received August 5, 2005; E-mail: sbuchwal@mit.edu
Table 2. Cyclization of 2-Phenylacetanilides
The prevalence of heterocycles in medicinally important com-
pounds continues to drive the need for new methods for their
preparation.1,2 The majority of nitrogen heterocycles are prepared
by processes in which a carbonyl is condensed with a nitrogen
nucleophile. An attractive alternative to this protocol is to construct
the heterocyclic ring and the C-N bond simultaneously by the
combination of a nitrogen-containing functional group and an arene,
alkene, or alkane. In this communication, we disclose a new method
in which the combination of an amide and an unactivated arene,
under palladium catalysis, can be used to efficiently produce a series
of carbazoles, the derivatives of which have important photophysical
and biological properties.3 The key feature of this method is the
combination of C-H functionalization and C-N bond-forming
processes.
Our group has a long-standing interest in the formation of
aromatic carbon-nitrogen bonds via both Pd- and Cu-catalyzed
combination of aryl halides and sulfonates with amines and related
nucleophiles.4 We wondered whether it would be possible to affect
a similar catalytic C-N bond formation in which a C-H bond
was directly “substituted”. In recent years, significant progress has
been made in combining selective C-H functionalization and C-C
bond-forming processes with the aid of a directing functional
group.5,6 Additionally, Stahl has described the synthetic equivalent
of replacing a C-H bond with a C-N bond in the combination of
phthalimide and aryl sulfonamide nucleophiles to both activated
and unactivated olefins.7,8 The directed ortho-functionalization of
acetanilides, pioneered by Tremont9 and elegantly employed in
recent years,10 provided a conceptual basis for our approach.
We began by studying the conversion of 2-acetaminobiphenyl
(1) to N-acetyl carbazole (2) using a combination of a palladium
precatalyst and a reoxidant (Table 1). Preliminary results suggested
that the use of a combination of 5% Pd(OAc)2 and a stoichiometric
Table 1. Screen of Reaction Conditions for Carbazole Synthesis
a Conditions: 5 mol % Pd(OAc)2, 1 equiv Cu(OAc)2, 1 atm O2, 12-24
Gas
atm
Time
(h)
Conv.
(%)
Yield
(%)a
h. b Isolated yield after silica gel chromatography, average of two runs.
Entry
Pd catalyst
Reoxidant
1
2
3
4
5
6
7
8
9
25% Pd(OAc)2
25% Pd(OAc)2
1 Cu(OAc)2
air
air
air
24
24
24
24
24
18
24
24
24
24
24
24
93 76
26 19
<3 0
16 10
97 93b
>99 92
82 70
31 21
38 27
>99 93
>99 93
>99 95
amount of Cu(OAc)2 at 120 °C under an atmosphere of air or
oxygen provided a near quantitative yield of 2 in toluene (Table 1,
entries 5 and 6). We later found that a catalytic amount of Cu-
(OAc)2 (10%, Table 1, entry 12) was sufficient to mediate the
reoxidation process in the presence of oxygen and deliver 2 in
comparable yields.
With these results in hand, we sought to examine the scope and
generality of the method. Following a procedure for the Suzuki-
Miyaura coupling reaction recently developed in our laboratory,11
a series of substituted analogues of 1 were prepared by using
2-haloacetamides and the appropriate aryl boronic acid. As can be
seen from the results in Table 2, the method tolerates substitution
1 Cu(OAc)2
1 benzoquinone Ar
1 Cu(OAc)2
1 Cu(OAc)2
1 Cu(OAc)2
1 Cu(OAc)2
25% Pd(OAc)2
5% Pd(OAc)2
5% Pd(OAc)2
5% Pd(O2CCF3)2
5% PdCl2
air
O2
O2
O2
O2
5% PdCl2(CH3CN)2 1 Cu(OAc)2
10
11
12
5% Pd(OAc)2
5% Pd(OAc)2
5% Pd(OAc)2
50% Cu(OAc)2 O2
25% Cu(OAc)2 O2
10% Cu(OAc)2 O2
a GC yield versus internal standard. b Average of two runs, isolated yield:
94%.
9
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J. AM. CHEM. SOC. 2005, 127, 14560-14561
10.1021/ja055353i CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Cyclization of Substituted 2-Arylacetanilides
compounds. The Pd(0) species are reoxidized to Pd(II) by Cu-
(OAc)2, thus completing the catalytic cycle. Similar to the Wacker
process,12 the reduced Cu species are reoxidized to Cu(II) in the
presence of oxygen and the acetic acid released from the palladation
reactions.
In summary, we describe the tandem directed C-H functional-
ization and amide arylation for the efficient construction of
substituted carbazoles. The products can be assembled in a simple
two-step protocol from readily available reagents. Future investiga-
tions will focus on further expanding the scope of the reaction and
gaining a mechanistic understanding of the process.
Acknowledgment. We thank Johnson & Johnson (Focused
Giving Grant), the National Cancer Institute (Cancer Training Grant
GM 5-T32-CAO9112-30), and the National Institutes of Health
(GM58160) for support of this work.
Supporting Information Available: Experimental procedures and
spectral data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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Scheme 1. Possible Reaction Pathway for Conversion of 1 to 2
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on the “upper” aromatic group. In particular, the presence of a
substituent adjacent to the acetamide moiety was inconsequential.
More in question was whether the method would tolerate the
presence of substituents on the ring undergoing substitution. As
the results shown in Table 3 attest, this process is compatible with
a variety of electron-withdrawing and electron-donating groups.
In cases where two regioisomeric products could be obtained
(Table 3, entries 9 and 10), the major carbazole product, as shown
in the table, was formed with excellent selectivity (16:1 and 18:1).
These results suggest that the ring-forming reaction may be
controlled by steric factors.
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On the basis of previous mechanistic studies in ortho-metalation
reactions,6 we propose a plausible reaction pathway, as shown in
Scheme 1. Pre-association of the amide moiety of 1 to Pd(OAc)2
facilitates the ortho-palladation process with concomitant release
of an acetic acid. The formation of the six-membered palladacycle
and subsequent reductive elimination leads to product 2 and Pd(0)
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